Novel host-directed molecules blunt SARS-CoV-2, influenza virus Premium

Novel host-directed molecules blunt SARS-CoV-2, influenza virus

Indian researchers have, for the first time, been able to synthesise small molecules that can effectively halt the infection of cells by SARS-CoV-2 and influenza viruses by targeting the hosts. The approach adopted by the researchers is vastly different from the one that is usually used for making antivirals. In place of antivirals that directly target the virus in question, the team, co-led by researchers at IISER Mohali and IIT Ropar, attempted the host-directed therapy. Till date, no approved host-directed drugs are available for either SARS-CoV-2 or influenza virus. 

In both cultured cells and animal studies, the small molecules that were synthesised by Dr. Prabal Banerjee’s team at the Department of Chemistry, IIT Ropar showed over 95% efficacy in halting the infection of cells by SARS-CoV-2 and influenza viruses. The results were published in  PLOS Pathogens.

While antivirals that target the virus become ineffective once the virus develops resistance, drugs that target the host cells to prevent the virus from infecting them, are expected to remain effective even when the virus evolves by accumulating mutations. 

There is already evidence that the current FDA-approved drugs for treating SARS-CoV-2 and influenza virus infection are losing their efficacy due to the emergence of drug-resistant virus strains. In host-directed therapy, the challenge is that molecules can very often turn out to be toxic to the host cells, the reason why this approach has not been widely adopted. 

The small molecules were not only effective (over 95%) against both SARS-CoV-2 and influenza viruses, they were not toxic to either cultured cells or mice even after prolonged exposure.

“We initially tested 28 compounds for their effectiveness in blocking influenza virus from infecting the lung cells. Of the 28 molecules screened, one molecule — 1,3-diphenylurea derivative (DPUD) — was able to block both SARS-CoV-2 and influenza virus infection by almost 100% in cells without being toxic to the cells,” recalls Dr. Prabal Banerjee, who is one of the corresponding authors. “This prompted us to synthesise 22 additional DPUDs. Five of the total 23 DPUDs were found to be highly effective against both viruses, while one molecule tested against influenza virus and two tested against SARS-CoV-2 in mice were found to be highly effective without causing toxicity to the animals.” 

“The discovery of host-directed DPUD molecules was serendipity,” says Nirmal Kumar, a PhD student from IISER Mohali and first author of the paper. “When we began this work in early 2020, we were looking for potent anti-influenza agents through high-throughput screening of small molecules. We identified DPUDs that efficiently blocked influenza infection. After several experiments, we realised that the small molecules (DPUDs) were host-directed and found that they block the cell entry pathway of influenza virus.”